Microwave assisted synthesis of dehydrated sugar derivatives hydroxymethylfurfural, levulinic acid, anhydrosugar alcohols, and ethers thereof

ABSTRACT

Methods for the production of dehydrated sugars and derivatives of dehydrated sugars using microwave (MW) irradiation and methods of purifying the same are described. The dehydrated sugars derivatives include 5-hydroxymethyl-2-furfural (HMF) and anhydrosugar alcohols such as sorbitans and isosorbide. The derivatives include HMF ethers, levulinic acid esters, and ether derivatives of the anhydrosugar alcohols. The described methods require lower reaction temperatures and shorter reaction times than similar non microwave mediated reactions known in the art. Typical reaction conditions are 120-210° C., and typical reaction times are 30 minutes or less.

PRIORITY CLAIM

This application is a continuation application of prior, co-pending U.S.application Ser. No. 13/811,759, filed Jan. 23, 2013 which is a 371application to PCT Application Serial No. PCT/U.S.2011/044324 filed Jul.18, 2011, which itself claims the benefit under 35 U.S.C. §119(e) ofU.S. Provisional Application Ser. No. 61/369,350, filed Jul. 30, 2010,which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to improved methods of producing thedehydrated sugar derivatives such as 2,5-(hydroxymethyl)furfural,levulinate esters, anhydrosugar alcohols as well as ether and esterderivatives thereof using microwave radiation to catalyze the reactions.

BACKGROUND

The principle sugars from plant materials, glucose and fructose, havebeen shown to be useful renewable starting materials for the productionof a variety of organic compounds that may substitute for petroleumbased compounds. For example, the furan compound,2,5-(hydroxymethyl)furaldehyde, also known as2,5-(hydroxymethyl)furfural (HMF) a five membered heterocycle obtainedby dehydration of a hexose, most efficiently from fructose.

HMF has strong potential in industrial and commercial applicationsespecially for polymer applications due to its multi-functionality whichallows for use as a monomer in polymerization reactions.

Generation of HMF by dehydration of fructose produces three equivalentsof water as by products, and the formation of 3 double bonds (twoalkenes and one aldehyde). In order to compete as substitutes orreplacements in the chemicals market, HMF must be produced at relativelylow cost. The production of HMF has been studied for years, but anefficient and cost-effective method of producing HMF has yet to befound. Extended reaction times, high temperatures and pressures causecomplications to arise from the rehydration of HMF after the dehydrationoccurs, which often yields the byproducts of levulinic acid and formicacid. Another competing side reaction is the polymerization of HMFand/or fructose to form humin.

A low yield of HMF is typically obtained when the synthesis is performedin aqueous conditions because of the low selectivity of the dehydrationreaction. Low selectivity simultaneously leads to increasedpolymerization reactions and humin formation, which also interfere withthe synthesis of HMF. Where attempts have been made to solve problemsassociated with aqueous systems, the HMF reaction product is generallysequestered by organic solvent extraction or adsorption onto a resin assoon as it is formed. These systems fail to directly address the issueof low selectivity for HMF. In addition, these systems generally sufferfrom high dilution or partially irreversible adsorption of HMF andincrease cost due to handling and use of the organic solvents or resins.Thus, a selective aqueous reaction system wherein HMF is the predominantproduct formed at would be desirable.

Levulinic acid is made by dehydration of hexose, which generates HMF asan intermediate, followed by deformylation resulting in the loss offormic acid. Levulinic acid and levulinate esters have been used asimportant intermediates in pharmaceutical and fine chemical processes.

Anhydrosugar alcohols, such as sorbitan and isosorbide derived fromglucose, are mono cyclic and bi-cyclic ring compounds that are made bythe dehydration of 1 or 4 water molecules, respectfully, from a hexitol,which is typically made by hydrogenation of a hexose.

Of all the known isohexides, isosorbide is considered to be one of highimportance because of its use in the formation of pharmaceuticalcompounds, in food production, cosmetic production, plastic and polymerproduction, and in other potential industrial uses such as in theproduction of polyurethane, polycarbonate, polyesters, and polyamides(Stoss and Hemmer, 1991).

Several processes for the production of anhydrosugar alcohols (includingisohexides such as isosorbide) have been reported. For example, PCTapplication number PCT/U.S.99/00537 (WO 00/14081), discloses collectingmethods and a continuous production method with recycling of organicsolvent. Most methods involve the use of concentrated acids and organicsolvents. Goodwin et al., Carbohydrate Res. 79:133-141 (1980) havedisclosed a method involving the use of acidic-cation-exchange resin inplace of concentrated, corrosive acids, but with low yield of isosorbideproduct. An alternative is the supersaturation-based method, asdisclosed in U.S. Pat. No. 4,564,692 (Feldmann, et al., Jan. 14, 1986).However, a need continues for a process for production of very puredianhydrosugar alcohols, at reasonable yields.

These dehydrated ring derivatives of hexoses, may further be used formaking several other compounds, for example, by making ether derivativesof the free alcohol groups as illustrated below:

For example, the anhydrosugar alcohol, isosorbide, can be used as astarting material in the formation of isosorbide dimethyl ether andisosorbide dinitrate or as an intermediate in various organic synthesisreactions. Isosorbide dimethyl ether is useful as an industrial solvent,a pharmaceutical additive, and in personal care products, whileisosorbide dinitrate is useful as a medication to relieve the pain ofangina attacks or reduce the number of such attacks by improving bloodflow to the heart.

Accordingly, there is a need in the art to find methods of making avariety dehydrated sugar compounds and derivatives thereof that is costeffective and efficient.

BRIEF SUMMARY

Methods of producing a variety of dehydrated sugar derivatives areprovided. Commonly, for any of the dehydrated sugar derivatives themethods include forming a reaction mixture comprising a solvent and areactant selected from the group consisting of a hexose, a sugaralcohol, and an anhydrosugar alcohol; and contacting the mixture withmicrowave radiation bringing it to temperature of between 130° C. and220° C. for a time sufficient to convert at least 40% of the reactantinto at least one desired dehydrated sugar derivative product.

In one aspect, the reactant is a hexose and the desired dehydrated sugarderivative is HMF. In a particular embodiment of this aspect, the hexoseis fructose. In a typical embodiment, the reaction mixture furtherincludes an acid catalyst.

In another aspect, the reactant is a sugar alcohol and the desireddehydrated sugar derivative is an anhydrosugar alcohol. In a particularembodiment of this aspect, the sugar alcohol is sorbitol and thereaction product is sorbitan or isosorbide. In a typical embodiment, thereaction mixture further includes an acid catalyst. In typical practicesthe temperature range is 130° C.-190° C.

In another aspect the reactant is a hexose, the reaction mix contains anR-alcohol and the reaction product is an ether of HMF. In a similaraspect, the product is a levulinate ester. Glucose is preferred formaking the levulinateesters. In a typical embodiment, the reactionmixture further includes an acid catalyst.

In those aspects where an acidic catalyst may be used, the catalyst isselected from the group consisting of a solid acid substrate and ahomogeneous acid.

In embodiments where an R-alcohol R can be an alkyl, allyl, cycloalkyl,or aryl group, and the desired dehydrated sugar derivative is selectedfrom the group consisting of an R-ether or R-ester of the desireddehydrated sugar derivative. In a typical practice, the e R-alcohol isthe solvent of the reaction mixture. In those embodiments where thereactant is a hexose the desired dehydrated sugar derivative is selectedfrom the group consisting of R-oxy HMF, and R acyl-levulinate.

In those aspects where an anhydrosugar alcohol is desired, in exemplaryembodiments the reactant is sorbitol, the reaction mixture contains anacid catalyst, the temperature is between 130° C. and 190° C. and thedesired dehydrated sugar derivative comprises a combination of sorbitanand isosorbide. Typically, the desired dehydrated sugar derivative ispredominantly sorbitan.

In certain embodiments where reactant is the anhydrosugar alcohol and itis desired to make an ether derivative of the anhydrosugar alcohol, thereaction mixture further contains R-carbonate where R is an alkyl,allyl, cycloalkyl, or aryl group, the solvent is not water, the reactionmixture contains an organic base catalyst, and the desired dehydratedsugar derivative is an R-anhydrosugar alcohol ether. In an exemplaryembodiment, isosorbide is the reactant and the dehydrated sugarderivative is mono- or di-R oxy isosorbide.

In most practices greater than 40%, or greater than 50% of the reactantis converted into the desired dehydrated sugar derivatives. Manyembodiments further include at least partially purifying the desireddehydrated derivative from the reaction mixture. In a typical practice,the partial purification includes adding an immiscible organic solventto the mixture thereby partitioning the dehydrated sugar derivative intoimmiscible organic solvent solution, collecting the partitionedimmiscible organic solvent, and evaporating the collected solvent toproduce an extract enriched in the desired dehydrated sugar derivative.Suitable immiscible organic solvent can selected from ethyl acetate,methyl t-butyl ether, diethyl ether, toluene, methyl ethyl ketone, ethyllactate, methyl isobutyl ketone, octanol, pentanol, butyl acetate,chloroform, and any combinations thereof. In a particularly desirableembodiment, the starting reactant is fructose, the dehydrated sugarderivative is HMF, the reaction mixture contains and acid catalyst, andthe reaction solvent is selected from a group consisting of:dimethylacetamide, dimethylformamide, N-methyl pyrrolidinone, and HMF ispurified by partitioning it from the reaction solvent into theimmiscible organic solvent.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a chart showing conversion of HMF from fructose usingmicrowave radiation according to a series of experiments performed inaccordance with one aspect of the present invention.

FIG. 2 is a chart showing the effect of microwave radiation on thedehydration of sugars in comparison to non-microwave methods.

DETAILED DESCRIPTION

Disclosed herein are methods of improved synthesis of dehydrated sugarderivatives and ethers and esters thereof. The disclosure is based onthe surprising discovery that microwave radiation increases yield andselectivity, while lowering the temperature and time needed to performdehydration and derivative reactions with sugars. Typically, when usedin the presence of a conventional catalyst for such reactions,temperatures in the range of 130 to 180° C. can be used for periods ofabout 30 minutes or less to obtain comparable yields and selectivityobtained at temperatures of 200-250° C. using the same reagents andcatalyst system without the microwave radiation. Because the temperatureis so much lower using the microwave enhance radiations, the catalyticfunction of the microwave energy must be more than just providing heatto the reaction mixture. FIG. 2 shows a direct comparison of totalproduct yields from sugar dehydration using microwave radiation vsnon-microwave methods. By microwave radiation, total product yields areenhanced. While not being bound by theory, it is believed that microwaveenergy preferentially activates the carbon-oxygen-hydrogen bondsinvolved in dehydration and hydrolytic condensation, thereby facilitatefaster dehydration and bond formation at lower energy levels thanrequired by conventional heating.

HMF and HMF derivatives, such as HMF ethers and esters, and levulinicacid and derivatives, such as levulinate esters are provided. Suchmethods provide the advantages of higher starting concentrations,enhanced reaction rates, high selectivity for the reaction product ofchoice, ease of manipulation, and precise control over reactionconditions. In certain embodiments, processes are disclosed involvingmicrowave exposure of reactants either in the presence of an aqueous ororganic solvent and may be performed with or without a catalyst.

Other than in the examples herein, or unless otherwise expresslyspecified, all of the numerical ranges, amounts, values and percentages,such as those for amounts of materials, elemental contents, times andtemperatures of reaction, ratios of amounts, and others, in thefollowing portion of the specification and attached claims, may be readas if prefaced by the word “about” even though the term “about” may notexpressly appear with the value, amount, or range. Accordingly, unlessindicated to the contrary, the numerical parameters set forth in thefollowing specification and claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains errornecessarily resulting from the standard deviation found in itsunderlying respective testing measurements. Furthermore, when numericalranges are set forth herein, these ranges are inclusive of the recitedrange end points (i.e., end points may be used). When percentages byweight are used herein, the numerical values reported are relative tothe total weight.

It should be understood that any numerical range recited herein isintended to include all sub-ranges subsumed therein. For example, arange of “1 to 10” is intended to include all sub-ranges between (andincluding) the recited minimum value of 1 and the recited maximum valueof 10, that is, having a minimum value equal to or greater than 1 and amaximum value of equal to or less than 10. The terms “one,” “a,” or “an”as used herein are intended to include “at least one” or “one or more,”unless otherwise indicated.

Any patent, publication, or other disclosure material, in whole or inpart, that is identified herein is incorporated by reference herein inits entirety, but is incorporated herein only to the extent that theincorporated material does not conflict with existing definitions,statements, or other disclosure material set forth in this disclosure.As such, and to the extent necessary, the disclosure as explicitly setforth herein supersedes any conflicting material said to be incorporatedherein by reference. Any material, or portion thereof, that is said tobe incorporated by reference herein, but which conflicts with existingdefinitions, statements, or other disclosure material set forth hereinwill only be incorporated to the extent that no conflict arises betweenthat incorporated material and the existing disclosure material.

As would be understood in the art, the term “microwave irradiation”refers to electromagnetic waves comprising frequencies of 300 Megahertz(MHz) to 300 Gigahertz (GHz). In certain embodiments, the microwaveirradiation range comprises an alternating current signal with afrequency in a range of 300 MHz to 300 GHz. In other embodiments, themicrowave irradiation comprises an alternating current signal with afrequency in the range of 300 MHz to 30 GHz. In still other embodiments,the microwave irradiation range comprises an alternating current signalwith a frequency in the range of 300 MHz to 3 GHz.

The starting materials for the reactions described herein are sources ofsugars and dehydrated sugar derivatives. Examples of sugar sources thatmay be converted to HMF or HMF ethers and levulinic acid esters as wellas combinations thereof, include, but are not limited to any source of asugar, including for example, any hexose, polysaccharides comprising atleast one hexose, pentose, corn syrup, a dissolved crystalline fructose,high-fructose corn syrup which is typically a 45 to 75% wt/wt mixture offructose with glucose made by isomerization of ordinary corn syrup,high-fructose corn syrup refinery intermediates and by-products such asmother liquor, ordinary corn syrup, which is the glucose syrup obtainedfrom direct hydrolysis of corn starch, process streams from makingfructose or glucose, sucrose, sugar cane molasses, and any combinationsthereof. The source of the sugar is not important because all sugarswill undergo the dehydrations and hydrolytic synthesis reactions toproduce the derivatives described herein, however, the reaction productsand selectivity of the reactions will of course vary with the particularsource of sugar. Where the desired reaction product is HMF or aderivative of HMF, it is preferred to use a source that contains largeramounts of fructose. Where the desired reaction product is a levulinicacid ester, the desired starting material should contain larger amountsof glucose.

The reactions provided herein are capable of producing relatively highyields of products As used throughout in the present disclosure herein,“reaction yield” is calculated using the equation (moles of HMFproduced/moles of fructose consumed)×100. Product purity is reported ona weight percent basis. For example, in certain embodiments, greaterthan 25% of the sugar can be converted to HMF or HMF ethers and estersand levulinic acid and levulinate esters, as well as combinationsthereof. In other embodiments, greater than 50% of the sugar, such ashexose, can be converted to HMF or HMF ethers and esters, as well ascombinations thereof. In yet other embodiments, greater than 70% or moreof the sugar, such as hexose, can be converted to HMF or HMF ethers andesters, as well as combinations thereof.

The present disclosure provides various features and aspects of theexemplary embodiments provided herein. It is understood, however, thatthe disclosure embraces numerous alternative embodiments, which may beaccomplished by combining any of the different features, aspects, andembodiments described herein in any combination that one of ordinaryskill in the art may find useful.

To synthesize HMF in a microwave reactor, a hexose source—mostpreferably one containing fructose—is combined with a solvent, andoptionally with a catalyst to form a mixture that irradiated withmicrowaves for a sufficient time to convert at least a portion of thesugar into HMF.

In certain embodiments, the reaction mixture includes an acid catalyst,Suitable examples of acid catalysts include homogenous acids such asdissolved inorganic acids, soluble organic acids, soluble Brønsted-Lowryacids, and heterogeneous solid acid catalysts, acidic ion-exchangeresins, acid zeolites, Lewis acids, acidic clays, molecular sieves, andany combinations thereof. In typical embodiments the homogeneous acidmay have a range of 0.1% to 10% by weight starting sugar. In typicalembodiments, the homogeneous acid may have a range of 1% to 10% byweight. In other embodiments, the homogeneous acid may have a range of0.1% to 5% by weight. The heterogeneous solid acid catalysts oftencomprise a solid material which has been functionalizing to impart acidgroups that are catalytically active. Solid acid catalysts may have abroad range of composition, porosity, density, type of acid groups, anddistribution of acid groups. Solid acid catalysts may be recovered andreused, optionally with a treatment to regenerate any activity that mayhave been lost in use. Some solid acid catalysts that may be usedinclude, but are not limited to, Amberlyst 35, Amberlyst 36, Amberlyst70, Amberlyst 15, Amberlyst 131 (Rohm and Haas, Woodridge, Ill.),Lewatit S2328, Lewatit K2431, Lewatit S2568, Lewatit K2629 (Sybron Corp,Birmingham, N.J.), Dianion SK 104, Dianion PK228, Dianion RCPI60,RCP21H, Relite RAD/F (Mitsubishi Chemical, White Plains, N.Y.), Dowex50WX4 (Dow Chemical) and any combination thereof. In certain embodimentsof the present disclosure, the solid acid catalyst may have a range of1% to 50% by weight. In some embodiments, the solid acid catalyst mayhave a range of 1% to 25% by weight. In other embodiments, the solidacid catalyst may have a range of 1% to 10% by weight.

In exemplary embodiments, either a heterogeneous solid acid catalystlike Amberlyst 35 resin, or a homogeneous acid catalyst exemplified byH₂SO₄ was used. In preferred reactions, the reaction contains fructose,is conducted in an organic solvent, the microwave radiation is used toraise and hold the temperature to between 120 and 170° C., typicallyfrom between 130 and 160° C. and reaction time is sufficient to convertat least 40% of the fructose to HMF in 15 minutes. In higher yieldreactions, the temperature is between 140 and 160° C., the time is lessthan 30 minutes—more like 20 minutes, and at least 65% of the fructoseis converted to HMF. Typically these reaction conditions were conductedusing a ramp up to temperature time of 1.5 to 3 minutes.

Suitable organic solvents for the reaction mixture are polar organicaprotic solvents. Examples of possible solvents include, but are notlimited to, 1-methyl-2-pyrrolidinone, dimethylacetamide,dimethylformamide, dimethyl sulfoxide, methyl ethyl ketone, methylisobutyl ketone, acetonitrile, propionitrile, and any combinationsthereof.

Suitable heterogeneous acids catalysts that may be used include, but arenot limited to, Amberlyst 35, Amberlyst 36, Amberlyst 70, Amberlyst 15,Amberlyst 131 (Rohm and Haas, Woodridge, Ill.), Lewatit 52328, LewatitK2431, Lewatit 52568, Lewatit K2629 (Sybron Corp, Birmingham, N.J.),Dianion SK 104, Dianion PK228, Dianion RCPI60, RCP21H, Relite RAD/F(Mitsubishi Chemical, White Plains, N.Y.), Dowex 50WX4 (Dow Chemical)and any combination thereof. In certain embodiments of the presentdisclosure, the solid acid catalyst may have a range of 1% to 50% byweight. In some embodiments, the solid acid catalyst may have a range of1% to 25% by weight. In typical embodiments, the solid acid catalyst isused at a range of 1% to 10% by weight of the starting sugar.

Suitable homogeneous acids that may be used include inorganic acids suchas such as H₂SO₄, H₃PO₄, HCl, as well as strong organic acids such asoxalic acid, levulinic acid, and p-toluene sulfonic acid.

Other catalysts not exemplified may also be used. These include, but arenot limited to boron trifluoride etherate, and metals, such as Zn, Al,Cr, Ti, Th, Zr, and V.

Although use of an organic solvent and a catalyst is preferred, neitherare necessary to obtain suitable yields. The reaction may, for example,be conducted in an aqueous solvent with or without added catalyst. Underaqueous conditions without catalyst, the reaction temperature should bebrought to about 200-210° C. using the microwave radiation, however, thetime should be shortened to less than 5 minutes to avoid rehydration andproduction of levulinic acid and other non selective by-products. Yieldsof greater than 50% HMF from fructose were obtained in an aqueoussolvent in the absence of acid catalyst at reaction temperatures of200-210° C. for 3 to 3.5 minutes after a 3 to 3.5 minute ramp up totemperature. When sulfuric acid is used in an aqueous solvent, thereaction temperature and can be reduced to 130-170° C. and the timeincreased to 10-20 minutes.

Table 1 and FIGS. 1 and 2 illustrate data from several experimentsshowing the production and yield of HMF from fructose with microwaveradiation under various conditions.

TABLE 1 Conversion of Fructose to HMF at lower temperatures in shortertime periods using microwave irradiation graphically illustrated inFigure 1. Experiment Acid Temp Time Water Fructose HMF UnknownConversion # (%) Solvent (C.) (min) (%) Yield (%) Yield (%) Yield (%)(%) 1 50% Amberlyst DMF 130 5 10.22 45.44 44.96 0.00 82.40 35 2 50%Amberlyst DMF 130 10 9.4 47.36 45.92 0.00 87.23 35 3 50% Amberlyst DMF130 15 8.35 39.05 42.06 10.55 69.00 35 4 50% Amberlyst DMAc 130 10 10.9660.37 29.24 0.00 73.77 35 5 50% Amberlyst DMAc 130 15 10.96 37.59 43.847.61 70.24 35 6 50% Amberlyst Water 130 15 76.38 100.00 0.00 0.00 0.0035 7 0.9% H2SO4 nmp 160 10 6.05 7.87 61.58 24.50 66.84 8 0.9% H2SO4 nmp160 20 7.09 4.27 69.47 19.16 72.57 9 0.9% H2SO4 nmp 160 30 7.48 3.7573.97 14.80 76.85 10 1.8% H2SO4 nmp 160 10 6.83 9.44 68.17 15.56 75.2711 1.8% H2SO4 nmp 160 20 6.86 3.03 77.68 12.43 80.10 12 1.8% H2SO4 nmp160 30 7.46 2.53 76.08 13.94 78.05 13 1.8% H2SO4 water 140 10 72.9854.52 20.02 25.43 44.08 14 1.8% H2SO4 nmp 140 20 6.24 4.88 65.00 23.8868.33 15 none water 200 3 89.68 15.96 56.10 27.94 66.75 16 none water210 3.5 90.94 7.56 51.12 41.32 55.30 17 none water 220 3.5 92.67 5.9426.26 67.81 27.91 18 none water 190 3 84.18 59.01 22.57 18.43 55.05

The data from this table summarizing relative conversion of fructose andproduction of HMF is

HMF ethers can also be made directly under similar reaction conditionsif fructose is used as the starting material and reaction solvent is analcohol. Any organic alcohol or alcohol mixture can be used, includingallyl, alkyl, aryl, and cycloalkyl alcohols. In most practicalembodiments a C1 to C8 alcohol would be used, such as methanol, ethanol,propanols, primary and branched alcohols, and amyl or isoamyl alcohol.

Exemplary HMF ethers, include, but are not limited to,ethoxymethylfurfural, butoxymethylfurfural, isoamyloxyfurfural, andmethoxymethylfurfural inter alia or any combination thereof. Inaddition, the reaction product may comprise corresponding HMF esters,exemplified, 5-acetoxymethylfurfural, inter alia and any combinationthereof.

The reaction mixture preferably contains a catalyst and exemplarycatalyst include the same heterogeneous and homogeneous acid catalyst inthe same amounts mentioned for HMF synthesis. Typical reactionconditions include irradiating the mixture containing fructose, thecatalyst and the alcohol solvent to bring it a temperature of between140 to about 200° C. for a time sufficient to convert at least 50% ofthe fructose to the HMF ether derivative of the alcohol solvent. Typicalreaction times are only 30 minutes or less. Temperatures toward thehigher end of the range will lead to production of more HMF ether, butalso more levulinic acid ester derivatives than lower temperatures.Thus, for example, when the reaction was conducted at 160° C. for 10minutes in the presence of isoamyl alcohol and H₂SO₄ catalyst, about 16%of the reaction product was to isoamyl levulinate and about 55% was theisoamyloxyfurfural derivative. At 200° C. for 30 minutes under the sameconditions, about 18% of the reaction product was to isoamyl levulinatebut about 59% was the isoamyloxyfurfural derivative.

Levulinic acid esters: To selectively make the levulinic acid esterderivatives, it is preferable to start with a sugar source that containslarger amounts of glucose. Formation of the levulinic acid esters alsoentails use of the heterogeneous or homogeneous acid catalyst and thesolvent again should be, or contain, the same type of alcohols mentionedabove from making HMF derivatives.

In typical embodiments, dextrose (glucose obtained by hydrolysis ofstarch) is combined with the alcohol and acid catalyst and heated to atemperature of between 130 and 200° C. by contact with microwaveradiation for a period of 15 to 45 minutes to yield a reaction productthat is at least 40% levulinate ester. In exemplary embodiments,dextrose in ethanol was combined with a heterogeneous acidic resin(Amberlyst 35) and heated to 170° C. for a period of 30 minutes after atemperature ramp-up period of 7 minutes. The product yield was typicallyabout 50% of ethyl levulinate from dextrose. Smaller side productsincluded HMF at about 12% and the HMF ether derivative, ethoxymethylfurfural at about 25.4%

Exemplary levulinic esters include, but are not limited to, butyllevulinate, ethyl levulinate, and isoamyl levulinate inter alia and anycombination thereof. In certain embodiments, reaction yields oflevulinate esters can be very high.

Extraction Steps. In certain embodiments, after an aqueous mixture ofsugar has been irradiated for a sufficient time to convert at least aportion of the sugar into HMF or derivatives including HMF esters, HMFethers, and levulinate esters, an immiscible organic solvent may beadded to the mixture, which can be filtered or unfiltered, therebypartitioning the HMF and its derivatives into an organic phase solution;the organic phase solution may be collected; and the solvent may beevaporated, e.g., under a reduced atmospheric pressure, from the organicphase solution to produce an extract enriched with HMF and itsderivatives or levulnic acid derivatives. Examples of organic solventsthat may be used include, but are not limited to, ethyl acetate, methylt-butyl ether, diether ether, toluene, methyl ethyl ketone, ethyllactate, methyl isobutyl ketone, octanol, pentanol, butyl acetate,chloroform, and any combination thereof. In addition, the aqueous phasemay be collected and the unreacted fructose can be irradiated again toproduce HMF and its derivatives and levulinate esters, or it can berecycled for another purpose disclosed herein or known in the art.

The disclosed extraction method is particularly advantageous, as iteliminates the need for a multi-step purification process, therebyimproving speed and efficiency while reducing costs and waste. Theextracted reaction products may then be used as a reactant source forfurther transformation into a variety of useful derivatives orrecrystallized to further increase the purity of the reaction product.

Anhydrosugar alcohols can also be efficiently made using microwaveradiation. To make anhydrosugar alcohols, the initial reagent istypically a sugar alcohol, particularly a hexitol, that is irradiatedfor a sufficient time to dehydrate the sugar alcohol into a mono- ordi-anhydrosugar alcohol. Examples of sugar alcohols that may beconverted to anhydrosugar alcohols include, but are not limited to,monoanhydro sugar alcohol, dianhydro sugar alcohol, hexose, fructose,sorbitol, erythritol, theitol, xylitol, arabitol, ribotol, mannitol,galactitol, iditol, lactitol, isomalt, maltitol, and any combinationsthereof.

The solvent can be an aqueous solvent or a polar organic solvent orcombinations of the same. Preferred polar organic solvents are aproticsolvent. Examples of possible solvents include, but are not limited to,1-methyl-2-pyrrolidinone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile,propionitrile, and any combinations thereof. The reaction mixturetypically also includes a heterogeneous or homogeneous acid a catalystas has been described herein before for HMF production.

A mixture containing the sugar alcohol with the optional catalyst isheated with microwave irradiation for a time and at a temperature neededto promote the dehydration of sugar alcohol into an anhydrosugaralcohol. For example, in certain practices, the process is performed ata temperature range of 130° C. to 200° C. In some other embodiments, atemperature range of 170° C. to 190° C. may be employed. In certainembodiments, the process may be performed at a time range of 3 to 45minutes. Typical embodiments employ a ramp up to temperature time in arange of 3 to 4 minutes. In typical embodiments, 30 minutes issufficient for of greater than 50% of the hexitol into a mixture ofmonoanhydro and dianhydrosugar alcohols. In a typical 30 minutereaction, the predominant reaction product is a mono anhydrosugaralcohol, exemplified by sorbitan. Longer reaction times will result infurther dehydration to produce greater amounts of the dianhydrosugaralcohol exemplified by isosorbide. It is anticipated that reaction timesof less than 2 hours will be sufficient to convert most of the hexitolinto the dianhydrosugar alcohol derivative.

Microwave assisted synthesis of isosorbide and sorbitan allows for theenhancement of reaction rates, ease of manipulation, and precise controlover reaction rates. Following preparation, the anhydrosugar alcoholsmay be further purified. One preferred purification is accomplished byuse of a film evaporator.

Anhydrosugar alcohol ethers can also be efficiently made from theanhydrosugar alcohols using microwave assisted irradiaton. Isosorbidedimethyl ether may be used for various applications including, but notlimited to, industrial solvents, pharmaceutical additives, and personalcare products.

One aspect of forming ethers from anhydrosugar alcohols is the use ofdialkyl carbonates at greatly reduced temperatures pressures, and times.In prior reactions, use of dialkyl carbonates to form the correspondingalkyl ether derivatives of isosorbide required temperatures of 240-260°C., pressures of 4 MPa, and reaction times of two hours or greater. Inthe present teaching, the reaction can be done by irradiating themixture with microwaves to temperatures as low as 120-170° C. in aslittle as 10-30 minutes. In an exemplary embodiment using isosorbide anddimethyl carbonate, the microwave power was 1000 watts, the reactiontemperature was 150° C. with a ramp-up to temperature time of 2 minutesand continued microwave exposure was use to maintain that temperaturefor only 15 minutes. Typically the starting anhydrosugar alcohol isdissolved in a dialkyl carbonate solvent, which also serves as thealkylating reactant, however any solvent that can dissolve the reactantsand products would be suitable so long as sufficient molar amounts ofdialkyl carbonate are present. The alkyl group of the dialkyl carbonatescan be of any length soluble in the solvent and may comprise aryl, orcycloalkyl or allyl moieties. A base catalyst is preferentially used.One exemplary base catalyst is dimethlyaminopyridine (DMAP). Other basesincluding non nucleophilic organic bases, sodium methoxide, solidsupported bases, basic resins, weak inorganic bases, and stronginorganic bases may also be applied. This method is very beneficial asit increases the selectivity of the reaction. For example, a weak basewould increase the product selectivity towards the monoalkylether.Alternatively, if a strong base is used, the dialkylether would befavored. Therefore, the choice of base would allow for more control overthe product selectivity.

Another derivative compound of isosorbide that can be made by a similarprocess is isosorbide dinitrate. Isosorbide dinitrate may be used forvarious applications including, but not limited to, medication torelieve the pain of angina attacks and reduce attacks by increasingblood flow to the heart. It is made by substituting dimethyl nitrate forthe dialkyl carbonate and otherwise conducting the same steps withmicrowave irradiation.

The various embodiments of the present disclosure may be betterunderstood when read in conjunction with the following examples.

EXAMPLES

The following examples illustrate various non-limiting embodiments ofthe compositions and methods of the present disclosure and are notrestrictive of the invention as otherwise described herein. Unlessotherwise indicated, all percentages are by weight. The yields disclosedherein are exemplary and do not reflect the optimal yields underoptimized conditions.

Example 1 Preparation Of HMF In Dimethylacetamide

A mixture of crystalline fructose (10 g) in dimethylacetamide (30 mL)and Amberlyst 35 wet resin (Rohm and Haas, Woodridge, Ill.) was placedin a sealed Teflon-lined-reaction vessel inside a high-density rotor fortreatment in a MicroSYNTH Microwave Labstation. The sample was heatedvia microwaves from room temperature to 65° C. in 1.5 min., then to 130°C. in 1 min., and kept at 130° C. for 15 min. using an irradiation powerof 1000 Watts. The vessel was cooled. Analysis indicates a 42% molaryield of HMF from fructose and 69% conversion (See Experiment 5 in Table1).

Example 2 Preparation Of HMF In Dimethylformamide

A mixture of crystalline fructose (10 g) in dimethylformamide (30 mL)and Amberlyst 35 wet resin (5 g, Rohm and Haas, Woodridge, Ill.) wasplaced in a sealed Teflon-lined reaction vessel inside a high-densityrotor for treatment in a MicroSYNTH Microwave Labstation. The sample washeated via microwaves from room temperature to 65° C. in 1.5 min., thento 130° C. in 1 min., and kept at 130° C. for 15 min. using anirradiation power of 1000 Watts. The vessel was cooled. Analysisindicates a 41% molar yield of HMF from fructose and 71% conversion (SeeExperiment 3 in Table 1).

Example 3 Preparation Of HMF In NMP

In a first experiment, a mixture of crystalline fructose (10 g) in NMP(25 mL) and concentrated H₂SO₄ (0.1 mL) was placed in a sealedTeflon-lined reaction vessel inside a high-density rotor for treatmentin a MicroSYNTH Microwave Labstation. The sample was heated viamicrowaves from room temperature to 140° C. in 3 min., and kept therefor 20 min. using an irradiation power of 1000 Watts. The vessel wascooled. Analysis indicates a 65% molar yield of HMF from fructose.

In another experiment, a mixture of crystalline fructose (10 g) in NMP(25 mL) and concentrated H₂SO₄ (0.1 mL) was placed in a sealedTeflon-lined reaction vessel inside a high-density rotor for treatmentin a MicroSYNTH Microwave Labstation. The sample was heated from roomtemperature to 160° C. in 3 min., and kept there for 20 min. using anirradiation power of 1000 Watts. The vessel was cooled. Analysisindicates a 77% molar yield of HMF from fructose. These same conditions,when performed with a conventional heating system, produced 65% molaryield of HMF.

In the third experiment, a mixture of crystalline fructose (10 g) in NMP(25 mL) and concentrated H₂SO₄ (0.05 mL) was placed in a sealedTeflon-lined reaction vessel inside a high-density rotor for treatmentin a MicroSYNTH Microwave Labstation. The sample was heated from roomtemperature via microwaves to 160° C. in 3 min. and kept there for 20min. using an irradiation power of 1000 Watts. The vessel was cooled.Analysis indicates a 70% molar yield of HMF from fructose (SeeExperiment 14 in Table 1). These same conditions, when performed with aconventional heating system, produced 54% molar yield of HMF.

Example 4 Preparation Of HMF In Water

In a first experiment, a mixture of crystalline fructose (10 g) in water(25 mL) and concentrated H₂SO₄ (0.1 mL) was placed in a sealedTeflon-lined reaction vessel inside a high-density rotor for treatmentin a MicroSYNTH Microwave Labstation. The sample was heated viamicrowaves from room temperature to 140° C. in 3 min., and kept therefor 10 min. using an irradiation power of 1000 Watts. The vessel wascooled. Analysis indicates a 20% molar yield of HMF from fructose and44% conversion

Example 5 Preparation Of HMF In Water

In a first experiment, a mixture of crystalline fructose (10 g) in water(40 mL) was placed in a sealed Teflon-lined reaction vessel inside ahigh-density rotor for treatment in a MicroSYNTH Microwave Labstation.The sample was heated from room temperature via microwaves to 200° C. in3 min., and kept there for 3 min. using an irradiation power of 1000Watts. The vessel vas cooled. Analysis indicates a 54% molar yield ofHMF from fructose and 63% conversion. These same conditions, whenperformed with a conventional heating system, produced 1% molar yield ofHMF.

In a second experiment, a mixture of crystalline fructose (10 g) inwater (40 mL) was placed in a sealed Teflon-lined reaction vessel insidea high-density rotor for treatment in as MicroSYNTH MicrowaveLabstation. The sample was heated from room temperature to 210° C. in3.5 min., and kept there for 3.5 min. using an irradiation power of 1000Watts. The vessel was cooled. Analysis indicates a 52% molar yield HMFfrom fructose and 55% conversion.

Example 6 Preparation Of Isoamyl HMF

In a first experiment, a mixture of crystalline fructose (10 g) inisoamyl alcohol (40 mL) and concentrated H₂SO₄ (0.10 mL) was placed insealed a Teflon-lined reaction vessel inside a high-density rotor fortreatment in a MicroSYNTH Microwave Labstation. The sample was heatedfrom room temperature via microwaves to 200° C. in 3 min., and keptthere for 3 min. using an irradiation power of 1000 Watts. The vesselwas cooled. Analysis indicates a 59% molar yield of isoamyl HMF and 18%yield of isoamyl levulinate from fructose.

In the second experiment, a mixture of crystalline fructose (10 g) inisoamyl alcohol (40 mL) and concentrated H₂SO₄ (0.10 mL) was placed in asealed Teflon-lined reaction vessel inside a high-density rotor fortreatment in a MicroSYNTH Microwave Labstation. The sample was heatedfrom room temperature via microwaves to 160° C. in 3 min., and keptthere for 20 min. using an irradiation power of 1000 Watts. The vesselwas cooled. Analysis indicates a 61% molar yield of isoamyl HMF and 27%yield of isoamyl levulinate from fructose. These same conditions, whenperformed with a conventional heating system, produced 33% molar yieldof isoamyl HMF and 24% molar yield of isoamyl levulinate.

In the third experiment, a mixture of crystalline fructose (10 g) inisoamyl alcohol (40 mL) and concentrated H₂SO₄ (0.10 mL) was placed in asealed Teflon-lined reaction vessel inside a high-density rotor fortreatment via microwaves in a MicroSYNTH Microwave Labstation. Thesample was heated from room temperature to 160° C. in 3.5 min., and keptthere for 10 min. using an irradiation power of 1000 Watts. The vesselwas cooled. Analysis indicates a 55% molar yield of isoamyl HMF and 16%yield of isoamyl levulinate from fructose.

Example 7 Purification Of HMF From A Reaction Mixture

The material prepared as described in Example 5 was filtered by gravityfiltration. Ethyl acetate (120 mL) was added to the solution, and twolayers separated. The organic layer was dried over M_(g)SO₄, and thesolvent evaporated to provide 3.36 g of bright red oil which was 64.4%HMF.

Example 8 Preparation Of Levulinate Ester

In a first experiment, a mixture of crystalline dextrose (4 g) inethanol (40 mL) and dry Amberlyst 35 resin (4 g) was placed in a sealedTeflon-lined reaction vessel inside a high-density rotor for treatmentvia microwaves in a MicroSYNTH Microwave Labstation. The sample washeated from room temperature to 170° C. in 7 min. and maintained at thistemperature for 30 min. using an irradiation power of 1000 Watts. Thevessel was then cooled. Analysis indicated a 49.4% molar yield of ethyllevulinate 12.3% molar yield of HMF and 3% molar yield ofethoxymethylfurfural from dextrose. These same conditions, whenperformed using conventional heating methods, provided 24% molar yieldof ethyl levulinate, 9% dextrose, and 2% yield of HMF.

In a second experiment, a mixture of crystalline dextrose (7 g) inethanol (70 mL) and dry Amberlyst 35 resin (7.02 g) was placed in asealed Teflon-lined reaction vessel inside a high-density rotor fortreatment via microwaves in a MicroSYNTH Microwave Labstation. Thesample was heated from room temperature to 170° C. in 7 min. andmaintained at this temperature for 30 min. using an irradiation power of1000 Watts. The vessel was then cooled. Analysis indicated a 49.3% molaryield of ethyl levulinate from dextrose.

In a third experiment, a mixture of crystalline dextrose (7 g) inethanol (70 mL) and dry Amberlyst 35 resin (3.54 g) was place in asealed Teflon-lined reaction vessel inside a high density rotor fortreatment via microwaves in a MicroSYNTH Microwave Labstation. Thesample was heated from room temperature to 170° C. in 7 min., and keptthere for 30 min. using an irradiation power of 1000 Watts. The vesselwas then cooled. Analysis indicated a 25.4% molar yield of ethyllevulinate from dextrose.

Example 9 Preparation Of Furfural

In an experiment, a mixture of crystalline xylose (10 g) in ethanol (50mL) and sulfuric acid (2% by wt of sugar) was placed in a sealedTeflon-lined vessel inside a high-density rotor for treatment viamicrowaves in a MicroSYNTH Microwave Labstation. The sample was heatedfrom room temperature to 170° C. in 4 min. and maintained at thistemperature for 20 min. using an irradiation power of 1000 Watts. Thevessel was then cooled. Analysis indicated a 27% molar yield of furfuralfrom xylose.

Example 10 Preparation Of Isosorbide From Sorbitol Using MicrowaveIrradiation At 170° C. And Sulfuric Acid

A 70% sorbitol solution (50 g) and concentrated sulfuric acid (0.20 mL)was placed in a TEFLON®-lined reaction vessel inside a high densityrotor for treatment in a MICROSYNTH® Microwave Labstation. The samplewas heated from room temperature to 170° C. in 3 minutes, and kept at170° C. for 30 minutes using microwave irradiation at a power of 1000watts. The reaction mixture was then cooled. The final product wascomposed of 50.4% sorbitan, 7.8% isosorbide, and 11.9% sorbitol.

Example 11 Preparation Of Isosorbide From Sorbitol Using MicrowaveIrradiation At 190° C. And Sulfuric Acid

A 70% sorbitol solution (50 g) and concentrated sulfuric acid (0.20 mL)was placed in a TEFLON®-lined reaction vessel inside a high densityrotor for treatment in a MicroSYNTH® Microwave Labstation. The samplewas heated from room temperature to 190° C. in 4 minutes, and kept at190° C. for 30 min using a microwave irradiation at a power of 1000watts. The vessel was cooled. The final product was composed of 39.6%sorbitan, 16.5% isosorbide, and 0.8% sorbitol.

Example 12 Preparation Of Isosorbide From Sorbitol Using MicrowaveIrradiation At 190° C. And Sulfuric Acid

A 70% sorbitol solution (50 g) and concentrated sulfuric acid (0.10 mL)was placed in a TEFLON®-lined reaction vessel inside a high densityrotor for treatment in a MicroSYNTH® Microwave Labstation. The samplewas heated from room temperature to 190° C. in 4 minutes, and kept at190° C. for 30 minutes using a microwave irradiation at a power of 1000watts. The vessel was cooled. The final product was composed of 43.4%sorbitan, 9.5% isosorbide, and 6.0% sorbitol.

Example 13 Preparation Of Dimethyl Isosorbide From Isosorbide

Isosorbide (3 g), dimethylaminopyridine (0.16 g), and dimethyl carbonate(30 mL) was placed in a Teflon-lined reaction vessel inside a highdensity rotor for treatment in a MicroSYNTH Microwave Labstation. Thesample was heated from room temperature to 150° C. in 2 min, and kept at150° C. for 15 min using an irradiation power of 1000 Watt. The vesselwas cooled. TLC analysis indicates a decrease in the amount ofisosorbide and a significant amount of dimethyl isosorbide. Monomethylisosorbide may also be present. The use of MW with dimethyl carbonate asa means of alkylating anhydrosugar alcohols is novel.

What is claimed is:
 1. A method of producing a dehydrated sugarderivative comprising, a. forming a reaction mixture comprising asolvent and a reactant selected from the group consisting of a hexose, asugar alcohol, and an anhydrosugar alcohol, wherein the reaction mixturedoes not contain a catalyst; and b. contacting the reaction mixture withmicrowave radiation to achieve a temperature of between 180° C. and 210°C. for a time sufficient to convert at least 40% of the reactant into atleast one desired dehydrated sugar derivative product.
 2. The method ofclaim 1 wherein the reactant is a fructose and the desired dehydratedsugar derivative is HMF.
 3. The method of claim 1 wherein the reactantis a sugar alcohol and the desired dehydrated sugar derivative is ananhydrosugar alcohol.
 4. The method of claim 1 wherein the solvent ofthe reaction mixture is water.
 5. The method of claim 1 wherein thereactant is a hexose and the desired dehydrated sugar derivative islevulinic acid.
 6. The method of claim 1 wherein greater than 50% of thereactant is converted to the desired dehydrated sugar derivative.
 7. Themethod of claim 1, further including at least partially purifying thedesired dehydrated derivative from the reaction mixture by at least:adding an immiscible organic solvent to the mixture, therebypartitioning the dehydrated sugar derivative into immiscible organicsolvent solution; collecting the partitioned immiscible organic solvent;and evaporating the collected solvent to produce an extract enriched inthe desired dehydrated sugar derivative.
 8. The method of claim 7,wherein the immiscible organic solvent is selected from the groupconsisting of ethyl acetate, methyl t-butyl ether, diethyl ether,toluene, methyl ethyl ketone, ethyl lactate, methyl isobutyl ketone,octanol, pentanol, butyl acetate, chloroform, and any combinationsthereof.
 9. The method of claim 1, wherein the reactant is fructose, thedehydrated sugar derivative is HMF, and the reaction solvent is selectedfrom a group consisting of: dimethylacetamide, dimethylformamide,N-methyl pyrrolidinone.